Preamble

Chinese General Practice: Traditional Chinese Medicine, Integrated Traditional and Western Medicine

The Impact of Integrated Traditional and Western Medicine on the Survival of Patients with Intermediate and Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies to treat globally, particularly when diagnosed at intermediate or advanced stages. In the field of Chinese general practice, the integration of Traditional Chinese Medicine (TCM) with Western medical protocols has emerged as a significant therapeutic strategy. This approach aims to leverage the strengths of both systems: the targeted, aggressive nature of Western interventions—such as transarterial chemoembolization (TACE), systemic chemotherapy, and molecular targeted therapies—and the holistic, regulatory benefits of TCM.

Recent clinical observations and research indicate that integrated traditional and Western medicine can significantly influence the prognosis of patients with intermediate and advanced HCC. While Western medicine focuses on tumor reduction and the inhibition of oncogenic pathways, TCM focuses on strengthening the patient's "Zheng Qi" (vital energy), alleviating treatment-induced toxicity, and improving the internal microenvironment. This synergy is hypothesized to not only improve the quality of life but also to extend the overall survival (OS) and progression-free survival (PFS) of patients who are often ineligible for curative resection.

[TABLE:1]

The therapeutic efficacy of this integrated approach is often measured through multi-dimensional indices. Beyond standard radiological responses, survival analysis serves as the gold standard for evaluating these interventions. Studies have shown that patients receiving integrated care often exhibit better tolerance to repeated cycles of Western treatments, such as TACE, due to the protective effects of TCM on hepatic function and the immune system. By mitigating the adverse effects of chemotherapy and targeted drugs, TCM allows for a more sustained and consistent treatment course, which is a critical factor in extending the survival of patients with advanced liver cancer.

[FIGURE:1]

Furthermore, the application of TCM in the management of HCC is increasingly being guided by modern pharmacological insights and machine learning models to predict patient outcomes. By analyzing complex datasets involving symptom patterns (syndrome differentiation) and clinical biomarkers, researchers are better able to tailor integrated treatment plans to the individual. This personalized approach in integrated medicine represents a frontier in improving the long-term survival rates of the intermediate and advanced HCC population, transitioning from a one-size-fits-all model to a more nuanced, patient-centric paradigm.

1.430061 湖北武汉，湖北中医药大学中医学院

Hubei Provincial Hospital of Traditional Chinese Medicine (Affiliated Hospital of Hubei University of Chinese Medicine), Wuhan, Hubei; Department of Hepatology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei; Hubei Key Laboratory of Traditional Chinese Medicine Liver and Kidney Research and Application, Wuhan, Hubei; Hubei Academy of Traditional Chinese Medicine, Wuhan, Hubei; Guangming Hospital of Traditional Chinese Medicine, Pudong New Area, Shanghai.

背景

Integrated traditional Chinese and Western medicine can effectively alleviate symptoms, inhibit tumor metastasis, and prolong the survival of patients with hepatocellular carcinoma (HCC). In recent years, with the advancement of evidence-based medicine, the definitive therapeutic efficacy of traditional Chinese medicine in treating liver cancer urgently requires support from real-world clinical data.

The objective is to understand the survival characteristics of patients with intermediate and advanced HCC and to explore the survival benefits of integrated traditional Chinese and Western medicine for this patient population.

方法

Clinical data were collected from 291 patients with intermediate-to-advanced hepatocellular carcinoma (HCC) who were hospitalized at Hubei Provincial Hospital of Traditional Chinese Medicine between December 2014 and May 2022, or who visited the same hospital and were enrolled in the "Primary Liver Cancer Bidirectional Cohort Study" between August 2023 and December 2024. Based on their treatment regimens, patients were divided into a Western medicine treatment group ($n=167$) and an integrated Traditional Chinese and Western medicine (TCWM) treatment group ($n=124$). Propensity score matching (PSM) was performed using the nearest neighbor matching method with a 1:1 ratio and a caliper value of 0.05 to screen patients. Kaplan-Meier survival curves were plotted to compare the 3-year survival and overall survival (OS) between the two groups. Furthermore, a Cox proportional hazards regression model was employed to analyze the factors influencing the survival period of HCC patients.

A total of 210 HCC patients were successfully matched, with 105 patients each in the Western medicine group and the integrated TCWM group. The matched cohort included 168 males (80.0%) and 42 females (20.0%), with a mean age of $57.7 \pm 0.8$ years. After matching, there were no statistically significant differences between the two groups in terms of gender, age, residence, smoking history, alcohol consumption history, presence of viral hepatitis, liver cirrhosis, diabetes, hypertension, or Barcelona Clinic Liver Cancer (BCLC) stage ($P > 0.05$). By the end of the follow-up period, 166 of the 210 patients (79.0%) had died, while 44 (21.0%) survived. The median survival time was 17.29 months (95% CI = 13.554–21.032). The cumulative 1, 3, and 5-year survival rates for the Western medicine group were 51.4%, 20.9%, and 7.3%, respectively, while those for the integrated TCWM group were 69.8%, 31.7%, and 10.9%. Statistically significant differences were observed between the two groups regarding both the 3-year survival and the survival period until the end of follow-up ($\chi^2 = 6.068, P = 0.014$; $\chi^2 = 5.171, P = 0.023$). Multivariate Cox regression analysis indicated that integrated TCWM treatment was associated with a reduced risk of death in patients with intermediate-to-advanced HCC compared to Western medicine treatment alone ($HR = 0.642, 95\% CI = 0.467–0.882, P = 0.006$).

The integration of local tumor therapy and/or targeted/immunotherapy can prolong the survival period and improve the survival rate of patients with intermediate-to-advanced HCC.

Keywords: Hepatocellular carcinoma; Intermediate and advanced stage; Hubei Province; Integrated Traditional Chinese and Western medicine; Cohort study; Propensity score matching; Cox regression
CLC Number: R 730.261
Document Code: A

Analysis of Factors Influencing the Survival Period of Patients with Intermediate and Advanced Hepatocellular Carcinoma Treated with Integrated Traditional Chinese and Western Medicine
LIN Ru$^{1}$, JUN Xiu$^{2,3,4}$, BAO Ping$^{2,3,4}$, YU Feng$^{2,3,4*}$
Hubei University of Chinese Medicine, Wuhan 430061, China

Hubei University of Chinese Medicine Wuhan 430061 China

Hubei Provincial Hospital of Traditional Chinese Medicine / Hubei Key Laboratory of Research and Application of TCM for Liver and Kidney Diseases Wuhan 430061 China Wuhan 430074 China Hospital Shanghai 201210 China

Chinese General Practice Meng Ren Attending Physician

Background

Integrated traditional Chinese and Western medicine treatment can effectively relieve symptoms，inhibit tumor metastasis，and prolong survival in patients with hepatocellular carcinoma（HCC）. In recent years， with the development of evidence-based medicine，the definite efficacy of traditional Chinese medicine in HCC treatment urgently requires support from real-world clinical data.

Objective To investigate the survival characteristics of patients with advanced HCC and explore the survival benefit of integrated traditional Chinese and Western medicine treatment for HCC patients.

Methods

Clinical data of 291 patients with advanced HCC were collected. These patients either were hospitalized in Hubei Provincial Hospital of Traditional Chinese Medicine from December 2014 to May 2022，or visited the same hospital and were enrolled in the "Bidirectional Cohort Study of Primary Liver Cancer" from August 2023 to December 2024. Patients were divided into two groups according to treatment regimens：the Western medicine treatment group（167 cases） and the integrated traditional Chinese and Western medicine treatment group（124 cases）. Propensity Score Matching（PSM） was performed using the nearest neighbor method at a 1∶1 ratio with a caliper value of 0.05 to screen patients. Kaplan-Meier survival curves were plotted to compare differences in 3-year survival and overall survival between the two groups receiving different treatments. A Cox proportional hazards regression model was used to analyze factors influencing the survival of HCC patients. Results：A total of 210 HCC patients were successfully matched，with 105 cases in each of the Western medicine treatment group and the integrated treatment group. Among them，there were 168 males（80.0%） and 42 females（20.0），with a mean age of（57.7±0.8） years. After matching，there were no statistically significant differences between the two groups in terms of gender，age，place of residence，smoking history，drinking history，presence of viral hepatitis，liver cirrhosis，diabetes，hypertension，or BCLC stage（ 0.05）. By the end of follow-up，166（79.0%） of the 210 patients had died and 44（21.0%） were still alive，with a median survival time of 17.29 months（95% =13.554-21.032）. The 1-year，3-year，and 5-year cumulative survival rates were 51.4%，20.9%，and 7.3% in the Western medicine treatment group，and 69.8%，31.7%，and 10.9% in the integrated treatment group，respectively. Statistically significant differences were observed between the two groups in 3-year survival and survival by the end of follow-up（χ =6.068， =0.014; χ =5.171， =0.023）. Results of the multivariate Cox regression model showed that compared with the Western medicine treatment group，the integrated traditional Chinese and Western medicine treatment reduced the survival risk of patients with advanced HCC（ 0.642，95% =0.467-0.882， =0.006）.

Conclusion

Traditional Chinese medicine combined with local tumor treatment and/or targeted/immunotherapy can prolong the survival time and improve the survival rate of patients with advanced HCC.

Primary liver cancer (PLC), commonly referred to as liver cancer, is a malignant tumor originating from hepatocytes or intrahepatic bile duct epithelial cells. It ranks as the sixth most common cancer globally and the third leading cause of cancer-related mortality. Hepatocellular carcinoma (HCC) accounts for approximately 90% of PLC cases, with a global 5-year survival rate of only 21%. According to statistics from the National Cancer Center, there were 367,700 new cases of HCC in China in 2022, with annual deaths reaching 316,500. Notably, China accounts for 45.3% of new HCC cases and 47.1% of HCC-related deaths worldwide, and the 5-year survival rate in the country is only 12.1%.

Liver cancer frequently develops on a foundation of cirrhosis. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), as well as cirrhosis resulting from long-term heavy alcohol consumption, are critical pathogenic factors. Approximately 80% to 90% of primary liver cancer cases occur in the context of hepatitis B-related cirrhosis. Currently, clinical treatment for HCC patients has entered a multidisciplinary team (MDT) diagnostic and therapeutic phase. The advantages and mechanisms of action of Traditional Chinese Medicine (TCM) in treating HCC patients have been extensively validated through numerous clinical and experimental studies \cite{7,8}.

However, high-level evidence-based medical data for integrated treatment regimens still require further refinement. This study focuses on the survival benefits of TCM combined with Western medicine for patients with intermediate-to-advanced HCC. To enhance the level of evidence, we employed propensity score matching (PSM) to address multiple confounding factors, effectively achieving "post-hoc randomization." This approach aims to provide a robust reference for clinical practice.

1.1 研究对象

Data were collected from 850 patients with hepatocellular carcinoma (HCC) hospitalized at Hubei Provincial Hospital of Traditional Chinese Medicine between December 2014 and May 2022, as well as 263 HCC patients who visited the same hospital and were enrolled in the "Bidirectional Cohort Study of Primary Liver Cancer" between August 2023 and December 2024. The inclusion criteria were as follows: (1) age $\ge 18$ years; (2) meeting the diagnostic criteria of the Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2022 Edition); (3) Barcelona Clinic Liver Cancer (BCLC) stage B or C; (4) complete clinical records, including clinical diagnostic information and treatment regimens; and (5) good patient compliance.

The exclusion criteria were as follows: (1) secondary liver cancer; (2) other pathological types of liver cancer, such as intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma;

Key words: HCC; Advanced Stage; Hubei Province; Integrated Traditional Chinese and Western Medicine (ITCM-WM) Treatment; Cohort Study; Propensity Score Matching; Cox Regression

(3) patients with severe comorbidities in other systems, such as the heart, brain, or lungs; (4) pregnant or lactating women; (5) patients receiving only symptomatic supportive care and/or Traditional Chinese Medicine (TCM) monotherapy; (6) patients with a survival time of no more than 7 days after diagnosis; and (7) patients deemed unsuitable for participation by the researchers. The protocol for this study has been reviewed and approved by the Ethics Committee of Hubei Provincial Hospital of Traditional Chinese Medicine (Approval No.: [Omitted]).

HBZY2023-C87-02）。

1.2.1 基线数据收集：（1）一般资料：包括性别、年

(1) Demographic and clinical characteristics, including age, place of residence, smoking history (defined as a history of smoking if the patient previously smoked but has quit, or currently smokes), and alcohol consumption history (defined as a history of alcohol use if the patient previously drank but has abstained, or currently drinks). Additional clinical factors include the presence of viral hepatitis, liver cirrhosis, diabetes, and hypertension. (2) Oncological indicators, including BCLC stage, tumor number, tumor size, portal vein tumor thrombus (PVTT), and extrahepatic metastasis. (3) Child-Pugh liver function classification (comprising assessments of ascites, hepatic encephalopathy, serum bilirubin, serum albumin, and prothrombin time extension).

1.2.2 临床治疗方案及分组：包括肝肿瘤切除术、局部

Treatments included transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), ablation therapy, radiotherapy, immunosuppressants and/or anti-angiogenic therapy (hereinafter referred to as "targeted and immunotherapy"), and Traditional Chinese Medicine (TCM). The Western Medicine (WM) group was defined as patients who received at least one instance of hepatic tumor resection and/or local therapy, and at least one cycle of targeted and immunotherapy, from the time of hepatocellular carcinoma (HCC) diagnosis until the end of follow-up.

The Integrated Traditional Chinese and Western Medicine (ITCWM) group was defined as patients who, in addition to the treatments received by the WM group, concurrently took TCM decoctions aimed at preventing tumor recurrence and metastasis or reducing toxicity and enhancing efficacy for a cumulative duration of $\ge 3$ months. Outcomes and follow-up indicators were as follows: (1) Outcome measure: Survival status (alive/deceased). Overall survival (OS) was calculated and defined as the time interval from the date of diagnosis until death or the end of follow-up. (2) Follow-up indicators: ① For the retrospective HCC cohort, patients recorded as surviving in electronic medical record discharge summaries were followed up four times between January 2023 and December 2024. ② For the bidirectional HCC cohort, follow-up was conducted monthly. Follow-up indicators included survival status and clinical treatment regimens. The follow-up deadline was December 31, 2024.

Data entry and verification files were established using EpiData 3.1 software. Data entry was performed by graduate students specializing in liver diseases who underwent standardized training prior to the process. HCC staging was evaluated by two physicians at the level of attending physician or above; any discrepancies were resolved by a physician at the level of associate chief physician or above. All HCC stages mentioned in this study refer to the BCLC stage at the time of diagnosis. Data cleaning and comparison were conducted by a dedicated data manager.

Statistical Methods

Statistical analysis was performed using SPSS 25.0 software. Quantitative data following a normal distribution are expressed as ($\bar{x} \pm s$); categorical data are described using relative numbers, and intergroup comparisons were performed using the $\chi^2$ test. Based on clinical experience, ten relevant factors—gender, age, residence, smoking history, alcohol consumption history, presence of viral hepatitis, liver cirrhosis, diabetes, hypertension, and BCLC stage—were selected to establish a Propensity Score Matching (PSM) logistic regression model. This model estimated the propensity score for each patient's predicted probability of receiving integrated treatment. Patients were matched using the nearest neighbor method (1:1 ratio, 0.05 caliper value) and divided into two groups: the WM group and the ITCWM group. Kaplan-Meier survival curves were plotted, and the Log-rank test was used to compare differences in the 3-year survival rate and the survival rate at the end of follow-up between the two groups. A Cox proportional hazards regression model was used to analyze factors influencing the survival of HCC patients. A $P$-value $< 0.05$ was considered statistically significant.

2.1 一般资料

The study initially identified 850 patients from a retrospective liver cancer cohort and 263 patients from a bidirectional liver cancer cohort. After excluding 386 patients with BCLC stage A or D, 53 overlapping cases between cohorts, 299 patients due to missing death dates or loss to follow-up, and 84 patients who received only symptomatic supportive care and/or traditional Chinese medicine (TCM) monotherapy, a final total of 291 patients were included in the analysis (the screening process is detailed in Figure 1 [FIGURE:1]).

Among the included participants, there were 235 males (80.8%) and 56 females (19.0%), with a mean age of $57.6 \pm 0.6$ years; patients aged 50–69 years accounted for 66.0% (192/291) of the total. The cohort was divided into a Western medicine treatment group (n=167) and an integrated Chinese and Western medicine treatment group (n=124). By the end of the follow-up period, 209 deaths were recorded, while 82 patients remained alive.

The study population was drawn from a retrospective liver cancer cohort of hospitalized HCC patients at our center between December 2014 and May 2022, as well as a bidirectional liver cancer cohort of HCC patients enrolled between August 2023 and December 2024. Exclusions were made for patients with BCLC stage A or D, overlapping cohort participants, those without recorded death dates, and those receiving only symptomatic supportive care and/or TCM treatment. The final analysis focused on HCC patients with BCLC stage B and C. (Flow chart of patient selection)

2.2 PSM

Before Propensity Score Matching (PSM), there were statistically significant differences between the Western medicine treatment group and the integrated Chinese and Western medicine treatment group regarding smoking status, alcohol consumption, presence of cirrhosis, and BCLC stage ($P < 0.05$). However, no statistically significant differences were observed between the two groups in terms of gender, age, place of residence, hypertension, diabetes, or history of viral hepatitis ($P > 0.05$).

To address these imbalances, a logistic regression model for PSM was established using the treatment modality as the dependent variable (assigned as: 0 = Western medicine group, 1 = integrated group). The independent variables included gender (male = 0, female = 1), age (40–49 years = 0, <40 years = 1, 50–59 years = 2, 60–69 years = 3, $\ge$70 years = 4), place of residence (urban = 0, town = 1, rural = 2), smoking history (no = 0, yes = 1), drinking history (no = 0, yes = 1), viral hepatitis (no = 0, yes = 1), cirrhosis (no = 0, yes = 1), diabetes (no = 0, yes = 1), hypertension (no = 0, yes = 1), and BCLC stage (Stage B = 0, Stage C = 1). Note that specific factors such as tumor number, tumor size, portal vein tumor thrombus, extrahepatic metastasis, and Child-Pugh grade were not individually included in the model, as they are already incorporated into the BCLC staging criteria. Propensity scores representing the predicted probability of receiving integrated treatment were estimated for each patient. Using a 1:1 matching ratio and a caliper value of 0.05, nearest neighbor matching was performed. This resulted in 105 successfully matched pairs (210 patients in total, with 105 patients in each group), as shown in [FIGURE:2].

Among the 210 patients after PSM, 168 were male (80.0%) and 42 were female (20.0%), with a mean age of $57.7 \pm 0.8$ years. Patients with a baseline of cirrhosis accounted for 76.7% (161/210). Regarding BCLC staging, 93 cases (44.3%) were Stage B and 117 cases (55.7%) were Stage C. Additionally, 25.2% (53/210) of patients underwent liver resection, 76.7% (161/210) received local therapy, and 51.9% (109/210) received targeted therapy and/or immunotherapy. In the integrated group, 50% (105/210) of the total matched cohort received Chinese herbal decoctions for $\ge$3 months. Following PSM, there were no statistically significant differences between the two groups in terms of gender, age, residence, smoking history, drinking history, viral hepatitis, cirrhosis at first diagnosis, diabetes, hypertension, or BCLC stage (all $P > 0.05$), as shown in [TABLE:1].

Follow-up and Survival Analysis

By the end of the follow-up period, 166 of the 210 patients (79.0%) had died, while 44 patients (21%) survived. The longest overall survival (OS) recorded was 124.34 months, and the shortest was 1.05 months.

The median survival time for the entire cohort was 17.29 months (95% CI = 13.554–21.032). The overall cumulative survival rates at 1, 3, and 5 years were 60.6%, 26.3%, and 9.1%, respectively. For the Western medicine group, the 1-, 3-, and 5-year cumulative survival rates were 51.4%, 20.9%, and 7.3%, respectively, compared to 69.8%, 31.7%, and 10.9% in the integrated Chinese and Western medicine group. Survival analysis indicated that the median survival time was 13.05 months (95% CI = 8.677–17.427) for the Western medicine group and 21.96 months (95% CI = 13.719–30.204) for the integrated group. This difference was statistically significant ($\chi^2 = 6.068, P = 0.014$). By the conclusion of the follow-up period,

2 组生存期比较，差异仍具有统计学意义（χ

($=5.171$, $=0.023$), as shown in Figure 3 [FIGURE:3].

2.4 HCC

Multivariate Cox proportional hazards regression analysis was conducted to identify factors influencing patient survival. Survival time (months) and survival status (assigned as: 0 = survived, 1 = deceased) were used as the dependent variables. The independent variables included age (assigned as: 40–49 years = 0, <40 years = 1, 50–59 years = 2, 60–69 years = 3, ≥70 years = 4), presence of cirrhosis (assigned as:

No = 0, Yes = 1), BCLC stage (assigned as: Stage B = 0, Stage C = 1), and treatment modality (assigned as: Western medicine group = 0, integrated Chinese and Western medicine group = 1). After adjusting for confounding factors such as gender, age, cirrhosis, and BCLC stage, the results of the multivariate Cox regression analysis indicated that, compared to the 40–49 age group, the risk of death was significantly higher in patients with mid-to-late stage HCC aged 50–59 years ($HR = 2.168$, $95\% CI = 1.274–3.690$, $P = 0.004$), 60–69 years ($HR = 2.273$, $95\% CI = 1.356–3.808$, $P = 0.002$), and $\ge 70$ years ($HR = 2.087$, $95\% CI = 1.075–4.050$, $P = 0.030$). Additionally, the presence of cirrhosis ($HR = 1.710$, $95\% CI = 1.168–2.504$, $P = 0.006$) and BCLC Stage C ($HR = 2.989$, $95\% CI = 2.129–4.197$, $P < 0.001$) were associated with an increased risk of death in mid-to-late stage HCC patients. Conversely, compared to the Western medicine group, the integrated Chinese and Western medicine group showed a significantly reduced risk of death ($HR = 0.642$, $95\% CI = 0.467–0.882$, $P = 0.006$) for patients with mid-to-late stage HCC, as shown in Table 2 [TABLE:2].

3 讨论

Introduction

Hepatocellular carcinoma (HCC) remains one of the most prevalent malignant tumors globally. Due to characteristics such as extensive tumor infiltration, diminished hepatic functional reserve, and a high propensity for distant metastasis, the middle and late stages of HCC represent a significant challenge in clinical practice. While current mainstream Western medical interventions—including targeted therapy, transarterial chemoembolization (TACE), and immunotherapy—can achieve short-term control of tumor progression, they are frequently associated with high rates of adverse reactions, further impairment of liver function, and limited long-term survival benefits.

Traditional Chinese Medicine (TCM) has accumulated extensive clinical experience in the treatment of liver cancer. However, there remains a lack of large-sample, long-term follow-up, real-world cohort studies regarding the survival benefits of integrated Chinese and Western medicine for patients with intermediate and advanced HCC. This deficiency significantly restricts the clinical promotion and standardization of such integrative approaches. Building upon our team's previous retrospective cohort studies, this research incorporates bidirectional cohort data to further analyze and compare the clinical outcomes between the Western medicine treatment group and the integrated Chinese and Western medicine treatment group.

25 A

Note: A represents the population pyramid before Propensity Score Matching (PSM), and B represents the population pyramid after PSM. [FIGURE:N] Population pyramids before and after PSM.

Chinese General Practice. Comparison of the baseline characteristics between two groups of patients before and after PSM. Before PSM: Western Medicine (WM) group, Integrated Traditional Chinese and Western Medicine (ITCWM) group. After PSM: WM group, ITCWM group. Note: PSM = Propensity Score Matching; BCLC = Barcelona Clinic Liver Cancer staging.

This study aims to evaluate the survival benefits of integrated therapy for patients with intermediate-to-advanced hepatocellular carcinoma (HCC) to provide higher-level evidence-based medical data for clinical practice. In this study, the male-to-female ratio was approximately 4.2:1, with the 50–69 age group accounting for the highest proportion (66%). This characteristic is largely consistent with the epidemiological data for HCC. Existing epidemiological studies have shown that the incidence of HCC peaks in the 60–70 age group, with males being the predominantly affected population \cite{}. Research suggests that male HCC patients may experience faster disease progression than females, or there may be differences in early symptom recognition and healthcare-seeking behavior, leading to a further increase in the proportion of males among patients with intermediate-to-advanced disease. Potential reasons for this gender disparity may be related to higher exposure to risk factors among men; for instance, smoking may increase the risk of liver cancer in males \cite{}. Furthermore, other studies have indicated that estrogen may maintain cholesterol homeostasis by upregulating Lecithin-Cholesterol Acyltransferase (LCAT), thereby inhibiting the development of liver cancer \cite{}. This may be one of the mechanisms underlying the lower risk of HCC in females.

In this study, 72.5% of HCC patients had underlying cirrhosis, which is highly consistent with the conclusions of previous studies \cite{}. For example, a 10-year follow-up cohort study of 2,079 patients with cirrhosis of various etiologies showed that 226 (9.4%) patients developed HCC during the follow-up period.

Chinese General Practice. Integrated Traditional Chinese and Western Medicine (ITCWM) group; Western Medicine (WM) group (after exclusion); ITCWM group (after exclusion). Cumulative survival rate (%). Multivariate Cox proportional-hazards regression analysis of factors influencing overall survival in patients with hepatocellular carcinoma.

Gender (Reference: Male); Age (Reference: 40–49 years).

<40 years; 0.262; 0.338; 0.600; 0.439; HR 1.299 (95% CI: 0.670–2.518).

≥70 years; 0.735; 0.338; 4.723; 0.030; HR 2.087 (95% CI: 1.075–4.050).

Underlying cirrhosis (Reference: No cirrhosis); BCLC stage (Reference: Stage B).

Stage C; 1.095; 0.173; 40.033; <0.001; HR 2.989 (95% CI: 2.129–4.197).

Treatment modality (Reference: Western Medicine group). Based on the aforementioned evidence, the timely diagnosis of cirrhosis and the implementation of regular HCC monitoring for high-risk populations are of critical importance for improving the prognosis of liver cancer. Combined with the baseline characteristics of this study—where males accounted for 80.8% and individuals over 50 years old accounted for 77%—it is further suggested that strengthening targeted screening for male cirrhosis patients over the age of 50 is essential for increasing the early detection rate of liver cancer and improving patient survival outcomes.

Surveys indicate that approximately 70%–85% of HCC patients have already lost the indications for radical surgery (such as liver resection or transplantation) at the time of initial diagnosis and must rely on comprehensive treatment to prolong survival \cite{}. As a treasure of Chinese heritage, Traditional Chinese Medicine (TCM) constitutes an important component of the comprehensive treatment of HCC \cite{}. At the end of the follow-up period in this study, the 1-, 3-, and 5-year cumulative survival rates of the ITCWM group (69.8%, 31.7%, and 10.9%, respectively) were higher than those of the WM group (51.4%, 20.9%, and 7.3%). The 3-year survival benefit was superior in the ITCWM group compared to the WM group (21.96 months vs. ...)

13.05 个月）；校正性别、年龄、肝硬化基础、BCLC 分

Integrated Traditional Chinese and Western Medicine Group vs. Western Medicine Group—After exclusion. Integrated Traditional Chinese and Western Medicine Group—After exclusion. Cumulative survival rate (%). After adjusting for confounding factors such as clinical stage, the risk of death for patients with intermediate-to-advanced hepatocellular carcinoma (HCC) treated with integrated traditional Chinese and Western medicine decreased by 35.8% ($HR = 0.642$, $95\% CI = 0.467\text{--}0.882$, $P = 0.006$). This survival benefit may be attributed to Traditional Chinese Medicine (TCM) regulating the function of immune cells within the tumor microenvironment. Specifically, TCM can inhibit the quantity and activity of pro-tumor immune cells, such as regulatory T cells and myeloid-derived suppressor cells \cite{17-18}, while enhancing the killing capacity of anti-tumor immune cells, such as natural killer cells and cytotoxic T lymphocytes, thereby inhibiting the progression of liver cancer \cite{19-20}. Furthermore, TCM may activate the tumor-suppressive signaling (p-Smad3C) of the TGF-$\beta$/Smad pathway or inhibit its pro-oncogenic signaling (p-Smad3L) to induce cell apoptosis \cite{21-22}. It is also associated with the inhibition of invasion and metastasis in liver cancer cells by blocking the epithelial-mesenchymal transition (EMT) and inhibiting matrix degradation and angiogenesis. Research has shown that by modulating the Hippo-YAP (Yes-associated protein) pathway and regulating the immune microenvironment, TCM can be combined with immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies) or conventional therapies (chemotherapy, radiotherapy) to enhance anti-tumor efficacy, reduce side effects, decrease drug resistance, and improve the quality of life for patients \cite{23-24}. The survival benefits of integrated traditional Chinese and Western medicine for intermediate-to-advanced HCC have been confirmed by multiple studies, with the core mechanism lying in the synergistic enhancement guided by the theory of "strengthening the body's resistance and eliminating pathogenic factors." In the field of targeted therapy, research by Zhang Zhen et al. \cite{25} demonstrated that the Yiqi Huayu Jiedu formula combined with sorafenib resulted in a higher 2-year survival rate for intermediate-to-advanced HCC compared to targeted therapy alone, confirming that TCM can enhance the anti-tumor effects of molecular targeted drugs. Regarding local ablation therapy, Wang Jianbin et al. \cite{26} found that patients in the high-exposure TCM group had a lower recurrence and metastasis rate two years after microwave ablation than the group without TCM intervention, reflecting the inhibitory effect of TCM on disease progression following minimally invasive treatment. In conventional medical treatment, research by Lyu Yanhang et al. \cite{27} indicated that Rougan Huaxian Jiedu granules combined with conventional therapy could improve the 12-month survival rate of patients with intermediate-to-advanced HCC, highlighting the incremental value of TCM to foundational treatments.

The aforementioned evidence suggests that TCM provides a critical survival guarantee for patients with intermediate-to-advanced HCC by reducing the risk of recurrence and metastasis, prolonging survival time, and enhancing tolerance to Western medical treatments.

The regulatory effect of patient age on the prognosis of intermediate-to-advanced HCC cannot be ignored. Survival time (months). Survival time (months). Note: A represents the 3-year survival curves for the two groups of patients; B represents the survival curves at the end of the follow-up period for the two groups; "After exclusion" refers to cases where the survival period was not reached during follow-up, and the intersection points represent patients who were still alive.

2 组患者Kaplan-Meier 生存曲线分析

Kaplan-Meier survival curves were compared between the two patient groups using the log-rank test.

Chinese General Practice. The results of this study indicate that compared to the 40–49 age group, the risk of mortality increased for those aged 50–59 ($OR = 2.168$, $95\% CI = 1.274\text{--}3.690$, $P = 0.004$), 60–69 ($OR = 2.273$, $95\% CI = 1.356\text{--}3.808$, $P = 0.002$), and $\ge 70$ years ($OR = 2.087$, $95\% CI = 1.075\text{--}4.050$, $P = 0.030$). Using restricted cubic spline analysis, Wang et al. identified a non-linear relationship between age at diagnosis and overall survival in patients with liver cancer, identifying 60 years as a critical turning point. Age $\ge 60$ years serves as an unfavorable prognostic factor, which is broadly consistent with our findings. This may be attributed to the decline in DNA mismatch repair capacity with advancing age, leading to increased gene mutation rates and tumor mutational burden. Furthermore, the heavy burden of comorbidities, physiological decline, and reduced hepatic drug clearance in elderly patients exacerbate the difficulty of treating liver cancer.

The results of this study demonstrate that patients with intermediate-to-advanced hepatocellular carcinoma (HCC) and underlying cirrhosis have a 71% higher risk of mortality compared to those without cirrhosis ($HR = 1.710$, $95\% CI = 1.168\text{--}2.504$, $P = 0.006$). A cancer registry-based study involving 9,753 cases found that liver cancer-specific survival was lower in patients with cirrhosis than in those without ($HR = 1.259$, $95\% CI = 1.166\text{--}1.358$, $P < 0.001$). The discrepancy in survival risk between that study and ours may be related to differences in the scope of the study populations. The adverse impact of underlying cirrhosis on the prognosis of liver cancer patients may be explained, on one hand, by the formation of a tissue-immune barrier (TIB) in cirrhosis, which inhibits T/NK cell function and induces M2 macrophage polarization, thereby weakening the regulatory capacity of the tumor microenvironment. On the other hand, cirrhosis induces cellular metabolic reprogramming (such as enhanced glycolysis) that supports tumor growth and drug resistance, promoting HCC progression and therapeutic resistance, which ultimately increases the risk of mortality.

This study found that clinical staging is a significant prognostic factor for liver cancer. Compared to patients with BCLC stage B, those with BCLC stage C had a 1.989-fold increase in mortality risk ($HR = 2.989$, $95\% CI = 2.129\text{--}4.197$, $P < 0.001$), which is consistent with the clinical utility of the BCLC staging system. A 2023 retrospective analysis from Vietnam showed that the median survival time for the BCLC stage B population was

13.5 个月，而C 期患者仅为4 个月

Furthermore, these results indicate that a later clinical stage is associated with a lower survival rate. A previous retrospective cohort study of 850 cases conducted by our research group also found that the 5-year survival rates for patients in BCLC stages B and C were significantly lower than those in BCLC stage A, highlighting the critical importance of early diagnosis and treatment.

This study has certain limitations. As a single-center real-world study, it is constrained by a relatively short follow-up period and a lack of comprehensive pathological indicators. Additionally, because the retrospective cohort spans a long period, data regarding the specific types and cycles of targeted or immunotherapy drugs, the frequency of local treatments, and the duration of traditional Chinese medicine (TCM) decoction use for deceased patients were incomplete. Consequently, a stratified analysis of different treatment combinations could not be performed, and evidence for optimizing specific treatment regimens was not provided. Furthermore, this study did not standardize the TCM prescriptions; instead, it aimed to reflect the actual state of clinical syndrome differentiation and treatment in practice. This approach was intended to explore the survival benefits of TCM involvement in the treatment of intermediate and advanced liver cancer and to provide a reference for selecting clinical treatment strategies.

The subjects of this study were patients with intermediate or advanced hepatocellular carcinoma (HCC) (corresponding to BCLC stage B or C) confirmed by pathological or clinical diagnosis, in accordance with the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition) \cite{1}. In this study, TCM interventions were administered alongside standard Western medical treatments (such as targeted therapy and interventional therapy), representing a "combined Chinese and Western medicine" scenario—where TCM is not used in isolation but as a synergistic component of Western treatment. Furthermore, because Propensity Score Matching (PSM) was employed to control for baseline differences, the results are most applicable to clinical scenarios where baseline characteristics (such as underlying cirrhosis, diabetes, hypertension, and BCLC stage) are similar to those of this study cohort. Clinical application should involve a comprehensive assessment of individual patient conditions, such as TCM syndrome types and tolerance to Western medical treatments. In summary, by utilizing a "retrospective + bidirectional" cohort design and rigorous confounding control methods, this study provides a reference for clinical decision-making in intermediate and advanced liver cancer. It clarifies the advantages of the integrated Chinese and Western medicine model, helping clinicians more rationally incorporate TCM into comprehensive treatment plans to avoid the misuse or omission of TCM due to insufficient evidence, thereby benefiting more patients with advanced HCC. The results of this study provide clear guidance for future research: subsequent efforts should focus on mechanistic studies (such as verifying the regulatory effects of TCM on the tumor microenvironment through cell experiments and animal models), individualized treatment research (developing precision TCM regimens based on syndrome differentiation), and optimization of combination therapies (identifying the optimal timing for combining TCM with targeted or immunotherapy). Additionally, quality of life assessments (such as the EORTC QLQ-HCC scale) should be included. Through multi-dimensional and multi-center research, the integrated Chinese and Western medicine treatment system can be continuously refined to promote high-quality development in the field of liver cancer treatment.

Author Contributions: Zhao Linru was responsible for the conception and design of the study and drafted the manuscript; Tao Junxiu proposed the primary research objectives and performed the revision of the manuscript; Luo Baoping was responsible for the implementation of the study; Shi Yufeng and Li Min performed data collection, organization, statistical processing, and the creation of figures and tables; Ren Meng was responsible for quality control and review of the article, held overall responsibility for the manuscript, and provided supervision and management.

The authors declare no conflicts of interest.

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